title: Fixed-dose combination fenofibrate/pravastatin 160/40 mg versus simvastatin 20 mg monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with simvastatin 20 mg: a double-blind, randomized comparative study.
abstract: BACKGROUND
  Patients with type 2 diabetes mellitus and mixed hyperlipidemia have an increased cardiovascular risk and may not achieve recommended LDL-C and non-HDL-C goals on statin monotherapy. This study was designed to obtain regulatory approval of a fenofibrate/pravastatin 160/40 mg fixed-dose combination (FDC) capsule.
  
  
  OBJECTIVE
  The aim of this study was to compare the efficacy and tolerability of this FDC and simvastatin 20 mg in patients with type 2 diabetes.
  
  
  METHODS
  This multicenter, randomized, double-blind, parallel-arm study was conducted in patients with type 2 diabetes and mixed hyperlipidemia, without cardiovascular disease, and who were not at lipid goals with simvastatin 20 mg monotherapy. After a 6-week run-in period during which patients received simvastatin 20 mg, those with non-HDL-C concentrations ≥130 mg/dL or LDL-C concentrations ≥100 mg/dL and triglyceride concentrations 150 to 600 mg/dL were enrolled. Eligible patients were randomly assigned to receive 12-week treatment with fenofibrate/pravastatin 160/40 mg FDC or simvastatin 20 mg once daily, followed by a 12-week open-label tolerability-assessment period during which all patients received the FDC. The primary efficacy outcome was the mean percentage change in non-HDL-C after 12 weeks. Secondary efficacy outcomes included changes in other lipid and lipoprotein parameters, fibrinogen, and high-sensitivity C-reactive protein. Tolerability was assessed based on the prevalence of adverse events and abnormal laboratory data in each treatment group.
  
  
  RESULTS
  A total of 291 patients were randomized to receive fenofibrate/pravastatin (n= 145) or simvastatin (n = 146). The mean (SD) age of the participants was 56.6 (8.9) years, 48.1% were men, and the body mass index was 31.3 (4.6) kg/m(2). The FDC was associated with a significantly greater reduction in non-HDL-C (primary end point) compared with simvastatin monotherapy (-12.9% [1.8] vs -6.8% [1.8]; P = 0.008). Triglyceride (-28.6% [3.7] vs +5.0% [3.6]; P < 0.001), fibrinogen (-11.5% [1.6] vs +0.3% [1.6]; P < 0.001), and HDL-C (+6.3% [1.3] vs +1.8% [1.3]; P = 0.008) concentrations also were significantly improved with the FDC compared with simvastatin monotherapy. The proportions of patients who achieved the LDL-C target (<100 mg/dL) were not significantly different between the 2 groups. The proportion of patients who achieved the combined end point of non-HDL-C <130 mg/dL and LDL-C <100 mg/dL was significantly greater with fenofibrate/pravastatin compared with simvastatin monotherapy (41 [28.5%] vs 26 [17.9%]; P < 0.05). The prevalences of patients who experienced ≥1 adverse event were not statistically different between the fenofibrate/pravastatin and simvastatin groups (17.2% vs 15.1%). However, compared with simvastatin monotherapy, the combination treatment was associated with significantly greater increases in alanine aminotransferase (+9.6% vs +1.5%; P = 0.03 between groups), creatinine (+13.7% vs +6.8%; P = 0.002 between groups), and homocysteine (+36.5% vs +1.6%; P < 0.001 between groups) concentrations.
  
  
  CONCLUSIONS
  In this selected population of adults with type 2 diabetes, the fenofibrate/pravastatin 160/40 mg FDC was associated with significantly greater changes from baseline in non-HDL-C, triglyceride, and HDL-C concentrations compared with simvastatin 20 mg. Both treatments were well tolerated.
authors.affiliation: Point Médical, Dijon, France. michelfarnier@nerim.net
authors.forename: Michel
authors.initials: M
authors.lastname: Farnier
authors.forename: Armin
authors.initials: A
authors.lastname: Steinmetz
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
authors.forename: Albert
authors.initials: A
authors.lastname: Császár
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D008076:Cholesterol, HDL / Q000187:drug effects; D008078:Cholesterol, LDL / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage* / Q000009:adverse effects; D005500:Follow-Up Studies; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000008:administration & dosage* / Q000009:adverse effects; D019821:Simvastatin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004338:Drug Combinations; D000960:Hypolipidemic Agents; D019821:Simvastatin; D017035:Pravastatin; D011345:Fenofibrate